Within the field of Alzheimer's Disease (AD) there are multiple theories of disease genesis. Although the hallmark physiological features- beta-amyloid plaques and tau neurofibrillary tangles- are diagnostic for the disorder, it is unknown whether the deposition of these proteins is the cause of neuronal death and cognitive symptoms. This proposal combines high resolution magnetic resonance imaging (MRI) of the hippocampal complex (HC) with two positron emission tomography (PET) techniques to investigate the relationship between protein deposition, HC neuronal loss and cortical thinning in subjects with and without the AD risk gene apolipoprotein E4. The first PET ligand studied, [F18]FDDNP, is a marker for beta-amyloid plaque and tau neurofibrillary tangle deposition; the second, [F18]MPPF binds to the serotionin 1A receptor, found specifically in pyramidal cells of the HC, and can be used as a measure of HC neuronal loss. The hippocampal complex is the primary site for formation of new memories, and is probably the first brain region showing AD-related changes in the early, preclinical stage. These two PET measures will be combined, in conjuction with a computational hippocampal unfolding technique developed by the Bookheimer laboratory, to identify physiological AD symptoms in the brain and HC long before serious cognitive symptoms have developed. We will compare protein deposition, cortical thining and neuronal loss in cognitively normal and mildly memory impaired older adults with and without a genetic risk for developing AD. These measures will be correlated with cognitive function assesed by neuropsychological testing. This research will help develop methods for identifying the first changes in AD, and will identify pathological features of AD that are most related to memory decline. This knowledge has strong implications for both early identification of AD and for identifying the optimal targets of early intervention. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common form of dementia and, according to the Center for Disease Control and Prevention, affects as many as five million Americans, surpassing diabetes to become the 6th leading cause of death among American adults; incidence increases with lifespan and the healthcare cost of this illness becomes astronomical, with AD affecting less than 13% of the Medicare population but responsible for 34% of Medicare spending (estimated to be $91 billion in 2005). Furthermore, by the time the disease symptoms are severe neuronal loss is extensive making recovery difficult at advanced stages. The goal of this research is to develop a better understanding of AD by combining positron emission tomography and magnetic resonance imaging to study the relationship between hallmark protein deposition and neuronal loss in subjects at risk for Alzheimer's disease before cognitive decline is apparent. This work will aid the development of sensitive and reliable methods of early AD detection that can be implemented long before symptoms emerge to drastically improve diagnosis and treatment. At the same time this investigation will contribute to our knowledge of the effects of healthy aging on human learning and memory.